Lung cancer is the leading cause of cancer death in both men and women in the United States. In 1998, an estimated 171,500 new cases were diagnosed, and about 160,100 deaths resulted from this disease. More women die from lung cancer than breast, ovarian, and uterine cancer combined, and 4 times as many men die from lung cancer than from prostate cancer. Most patients who are diagnosed with NSCLC cannot be cured with surgery and will eventually die from their disease. See SEER Cancer Statistics Review 2001. The median survival of patients with untreated metastatic NSCLC is only four to five months with a survival rate at one year of only 10 percent. Rapp E. et al. J Clin Oncol. 1988; 6:633-41.
Chemotherapy only moderately improves the median survival time (MST) of patients with locally advanced or metastatic NSCLC when compared to best supportive care (BSC). The first generation of chemotherapy agents extended the survival of patients with stage IIIB and IV NSCLC by 10% to 15%, when compared to BSC. Several meta-analyses indicate that cisplatin-containing regimens confer an increase of 6 to 8 weeks in MST and of 15% to 25% in 1-year survival. See Non-Small Cell Lung Cancer Collaborative Group. Br Med J. 1995; 311:899-909; Grilli R. et al. J Clin Oncol. 1993; 11:1866-1872; Souquet P. J. et al. Lancet 1993; 342:19-21. The most commonly used agents to treat NSCLC include carboplatin (response rate (RR): 20%-25%; see Bonomi P. D. et al. J Clin Oncol. 1989; 7:1602-13), paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® (RR: 20%-25%; see Gatzemeier U. et al. Lung Cancer. 1995; 12(Suppl 2):S101-5106; Hainsworth J. D. et al. J Clin Oncol, 1995. 13(7):1609-1614), docetaxel (RR: 23%-33%; see Fossella F. V. et al. J Clin Oncol. 1995; 13(3):645-651; Cerny T. et al. Br J Cancer. 1994; 70:384-387), gemcitabine (RR: 20%-25%; see Shepherd F. A. Anticancer Drugs. 1995; 6(Suppl 6):9-25; Sorensen J. B. Lung Cancer. 1995; 12 (Suppl 1):5173-5175), and vinorelbine (RR: 29.4%; see Depierre A. et al. Proc ASCO, 1988. 7:201). The MST for these drugs varies from 7.5 to 9.5 months.
Most treatment combinations to date center on the use of platinum-based regimens. Platinum-based agents are alkylating agents which bind covalently to DNA and cross-links DNA strands, resulting in inhibition of DNA synthesis and function as well as inhibition of transcription. Platinum-based chemotherapy combinations have demonstrated improvements over single-agent therapy in advanced NSCLC. See Dubey S. and Schiller J. H. Hematol Oncol Clin N Am. 2004; 18:101-114. For example, paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® (200-225 mg/m2) in combination with carboplatin (area under curve (AUC)=6) administered q3w is a commonly used and well accepted treatment regimen for patients with NSCLC, producing objective response rates in Phase III studies of 17%, 25%, 29%, 32%, and 37%. See Schiller J. H. et al. N Engl J Med. 2002; 346:92-98; Kelly K. et al. J Clin Oncol. 2001; 19:3210-3218; Herbst R. S. et al. J Clin Oncol. 2004; 22:785-794; Scagliotti G. V. et al. J Clin Oncol. 2002; 20:4285-4291; Lilenbaum R. C. et al. Presented at: American Society of Clinical Oncology (ASCO), June 2002. Abstract 2. Toxicities associated with this regimen were similar in nature to those associated with paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® and carboplatin individually, and the combination demonstrated no new or unexpected toxicities. The efficacy parameters were similar between paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® 100 mg/m2 weekly for 3 of 4 weeks with carboplatin AUC=6 and paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® 100 mg/m2 and carboplatin AUC=6 on day 1 of each 3-week cycle. See Belani et al. J Clin Oncol. 2008; 26(3):468-473.
A recent Phase III study comparing carboplatin/paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® to other doublets (cisplatin/paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® vs. cisplatin/gemcitabine vs. cisplatin/docetaxel vs. carboplatin/paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL®) demonstrated that all the combinations have similar efficacy. See Schiller J. H. et al. N Engl J Med. 2002; 346:92-98. However, because of its more favorable safety profile, the Eastern Collaborative Oncology Group (ECOG) selected carboplatin/paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® as its reference regimen for future studies. See Schiller J. H. et al. N Engl J Med. 2002; 346:92-98.
Paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® (Bristol-Myers Squibb Co., Princeton, N.J.) contains the chemotherapeutic active agent paclitaxel. Paclitaxel binds to the β-subunit of tubulin, the building blocks of microtubules, causing hyper-stabilization of the microtubule structures. The resulting paclitaxel/microtubule structure is unable to disassemble, thereby arresting mitosis and inhibiting angiogenesis. Because paclitaxel is highly hydrophobic, commercially available formulations include synthetic solvents to enable parenteral administration: paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® contains a combination of polyoxyethylated castor oil, sold under the trademark CREMOPHOR® EL and ethanol as paclitaxel vehicle.
The solvent used in paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® raises major concerns due to its intrinsic negative properties. Emerging data indicate that polyoxyethylated castor oil, sold under the trademark CREMOPHOR® is a biologically and pharmacologically active compound that directly contributes to the severe toxicities observed in patients treated with paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL®. Among the well-characterized, solvent-related toxicities are severe hypersensitivity reactions (which can be fatal even with steroid premedication); histamine release; and prolonged, sometimes irreversible peripheral neuropathy associated with demyelination and axonal degeneration. See Gelderblom H. et al. Eur J Cancer. 2001; 37:1590-8. Review; Lorenz W. et al. Agents and Actions 1977; 7:63-67; Weiss R. B. et al. J Clin Oncol. 1990; 8:1263-1268. Furthermore, these solubilizers adversely affect efficacy due to entrapment of active drug in micelles formed in the plasma compartment. See ten Tije A. J. et al. Clin Pharmacokinet. 2003; 42:665-85. Review. Such entrapment alters drug pharmacokinetics (PK), leading to highly increased systemic drug exposure, decreased drug clearance, nonlinear PK, and lack of dose-dependent antitumor activity. See ten Tije A. J. et al. Clin Pharmacokinet. 2003; 42:665-85. Review; Winer E. et al. Proceedings of ASCO 1998, Vol 17, Abstract 388; Sparreboom A. et al. Cancer Res. 1999; 59(7):1454-1457; van Tellingen O. et al. Br J Cancer. 1999; 81:330-5. Drug entrapment affects not only the taxanes but also co-administered drugs (e.g., anthracyclines, platinum compounds) and, thus, is an important consideration in the design of combination therapies. See ten Tije A. J. et al. Clin Pharmacokinet. 2003; 42:665-85. Review.
As emerging data have indicated that the solvent used in paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® may negatively impact the efficacy and toxicity profile of chemotherapy comprising paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL®, new paclitaxel formulations have been developed. Nab-paclitaxel (or ABI-007), sold under the trademark ABRAXANE®; Abraxis BioScience, Los Angeles, Calif.) is a novel, solvent-free, non-crystalline, amorphous, albumin-bound, paclitaxel particle with a mean size of approximately 130 nm suspended in normal saline See, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; 6,749,868, 6,537,579, and 7,820,788 and also in U.S. Pat. No. 8,034,375. Nab-paclitaxel is the first of a new class of anticancer agents that incorporate particle technology and exploit the unique properties of albumin, a natural carrier of lipophilic molecules in humans. Nab-paclitaxel utilizes the albumin receptor (gp60)/caveolin-1 (CAV1) pathway achieving high intratumoral paclitaxel accumulation. See Desai et al. Clin Cancer Res 2006; 12(4):1317-1324. Nab-paclitaxel has advantages compared to paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL® with regards to reduced toxicity, greater ease of administration, shorter drug infusion time, and avoidance of hypersensitivity reactions.
Nab-paclitaxel, when administered at a dose of 260 mg/m2 every 3 weeks to 43 patients with NSCLC as first-line therapy, resulted in an objective response rate of 16% with an additional 49% of patients achieving disease control (defined as stable disease for at least 16 weeks plus objective responses) and was well tolerated with no patients developing any Grade 4 toxicity at any time during the treatment course. See Green M. R. et al. Ann Oncol. 2006; 17:1263-8. When Nab-paclitaxel was given at a dose of 125 mg/m2 weekly for 3 weeks followed by one week off to 40 elderly patients with Stage IV NSCLC (median age 70), the objective response and disease control rates were 30% and 50% respectively. See Rizvi N. A. et al. J Clin Oncol., 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, No 18S (June 20 Supplement), 2006: 7105.
A high monotherapy response rate does not necessarily translate into a significantly higher combination therapy response rate in a Phase III trial, let alone result in additive efficacy. See Lynch et al. J Clin Oncol. 2010; 28(6):911-917 (“More than a dozen phase III trials have unsuccessfully investigated targeted approaches combined with platinum doublets.”).
In view of the improved objective response rates compared to paclitaxel dissolved in polyoxyethylated castor oil and dehydrated alcohol, sold under the trademark TAXOL®, Nab-paclitaxel was combined with carboplatin to evaluate efficacy and toxicity in NSCLC. In 100 patients treated with carboplatin (area under curve (AUC)=6) plus Nab-paclitaxel every 3 weeks at doses between 225 and 340 mg/m2, the overall response rate was 27% (see Hawkins M. J. et al. J Clin Oncol., 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, No 18S (June 20 Supplement), 2006: 7132) and a 50% response rate was reported using 100 mg/m2 Nab-paclitaxel weekly in combination with carboplatin in NSCLC patients (see Allerton J. P. et al. J Clin Oncol., 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, No 18S (June 20 Supplement), 2006: 7127). Further, in another study, NSCLC patients with histologic confirmation of adenocarcinoma receiving Nab-paclitaxel weekly in combination with carboplatin achieved a 59% ORR while NSCLC patients with histologic confirmation of squamous cell carcinoma achieved a 39% ORR. See Socinski M. A. et al. IASLC, 13th Word Conference on Lung Cancer. San Francisco, Calif.; Jul. 31-Aug. 4, 2009.
Further data is emerging that NSCLC is a diverse cancer with treatment and survival outcomes often dependent upon the histology of the malignancy and the molecule profile of the NSCLC. For example, survival analysis has previously shown a significant association of stromal Secreted Protein Acidic and Rich in Cysteine (SPARC) (also known as osteonectin and BM40) with markers of hypoxia/acidity and with poor prognosis in non-small cell lung cancer. See Koukourakis et al. Cancer Research. 2003. 63:53756-5380. In addition, previous studies also have indicated that histology can be an important predictor for clinical response. In a NSCLC Phase III trial comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed, for example, the use of cisplatin and pemetrexed in patients with adenocarcinoma and large-cell carcinoma resulted in significantly better survival than cisplatin and gemcitabine therapy while no significant difference was observed in squamous cell carcinoma. See Scagliotti et al. J Clin Oncol. 2008; 26(21)3543-3551. Squamous cell carcinoma of the lung accounts for one-third of primary lung cancer and a common malignant tumor with poor prognosis. In squamous cell carcinoma, advanced pathologic stage and poor prognosis have been correlated with increased caveolin-1 expression. Yoo et al. Lung Cancer. 2003 42:195-202.
The continued evaluation of new approaches to treat NSCLC is imperative to increase survival and quality of life of for NSCLC patients.
The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.